The Role of Alpha 6 Integrin in Prostate Cancer Migration and Bone Pain in a Novel Xenograft Model

Of the estimated 565,650 people in the U.S. who will die of cancer in 2008, almost all will have metastasis. Breast, prostate, kidney, thyroid and lung cancers metastasize to the bone. Tumor cells reside within the bone using integrin type cell adhesion receptors and elicit incapacitating bone pain and fractures. In particular, metastatic human prostate tumors express and cleave the integrin A6, a receptor for extracellular matrix components of the bone, i.e., laminin 332 and laminin 511. More than 50% of all prostate cancer patients develop severe bone pain during their remaining lifetime. One major goal is to prevent or delay cancer induced bone pain. We used a novel xenograft mouse model to directly determine if bone pain could be prevented by blocking the known cleavage of the A6 integrin adhesion receptor. Human tumor cells expressing either the wildtype or mutated A6 integrin were placed within the living bone matrix and 21 days later, integrin expression was confirmed by RT-PCR, radiographs were collected and behavioral measurements of spontaneous and evoked pain performed. All animals independent of integrin status had indistinguishable tumor burden and developed bone loss 21 days after surgery. A comparison of animals containing the wild type or mutated integrin revealed that tumor cells expressing the mutated integrin resulted in a dramatic decrease in bone loss, unicortical or bicortical fractures and a decrease in the ability of tumor cells to reach the epiphyseal plate of the bone. Further, tumor cells within the bone expressing the integrin mutation prevented cancer induced spontaneous flinching, tactile allodynia, and movement evoked pain. Preventing A6 integrin cleavage on the prostate tumor cell surface decreased the migration of tumor cells within the bone and the onset and degree of bone pain and fractures. These results suggest that strategies for blocking the cleavage of the adhesion receptors on the tumor cell surface can significantly prevent cancer induced bone pain and slow disease progression within the bone. Since integrin cleavage is mediated by Urokinase-type Plasminogen Activator (uPA), further work is warranted to test the efficacy of uPA inhibitors for prevention or delay of cancer induced bone pain

Current Issues in Environmental Law

Materials from the Current Issues in Environmental Law seminar held by UK/CLE in April 1995

Multilevel analysis in CSCL Research

Janssen, J., Erkens, G., Kirschner, P. A., & Kanselaar, G. (2011). Multilevel analysis in CSCL research. In S. Puntambekar, G. Erkens, & C. Hmelo-Silver (Eds.), Analyzing interactions in CSCL: Methods, approaches and issues (pp. 187-205). New York: Springer. doi:10.1007/978-1-4419-7710-6_9CSCL researchers are often interested in the processes that unfold between learners in online learning environments and the outcomes that stem from these interactions. However, studying collaborative learning processes is not an easy task. Researchers have to make quite a few methodological decisions such as how to study the collaborative process itself (e.g., develop a coding scheme or a questionnaire), on the appropriate unit of analysis (e.g., the individual or the group), and which statistical technique to use (e.g., descriptive statistics, analysis of variance, correlation analysis). Recently, several researchers have turned to multilevel analysis (MLA) to answer their research questions (e.g., Cress, 2008; De Wever, Van Keer, Schellens, & Valcke, 2007; Dewiyanti, Brand-Gruwel, Jochems, & Broers, 2007; Schellens, Van Keer, & Valcke, 2005; Strijbos, Martens, Jochems, & Broers, 2004; Stylianou-Georgiou, Papanastasiou, & Puntambekar, chapter #). However, CSCL studies that apply MLA analysis still remain relatively scarce. Instead, many CSCL researchers continue to use ‘traditional’ statistical techniques (e.g., analysis of variance, regression analysis), although these techniques may not be appropriate for what is being studied. An important aim of this chapter is therefore to explain why MLA is often necessary to correctly answer the questions CSCL researchers address. Furthermore, we wish to highlight the consequences of failing to use MLA when this is called for, using data from our own studies

Developing argumentation skills in mathematics through computer-supported collaborative learning: the role of transactivity

Collaboration scripts and heuristic worked examples are effective means to scaffold university freshmen’s mathematical argumentation skills. Yet, which collaborative learning processes are responsible for these effects has remained unclear. Learners presumably will gain the most out of collaboration if the collaborators refer to each other’s contributions in a dialectic way (dialectic transactivity). Learners also may refer to each other’s contributions in a dialogic way (dialogic transactivity). Alternatively, learners may not refer to each other’s contributions at all, but still construct knowledge (constructive activities). This article investigates the extent to which constructive activities, dialogic transactivity, and dialectic transactivity generated by either the learner or the learning partner can explain the positive effects of collaboration scripts and heuristic worked examples on the learners’ disposition to use argumentation skills. We conducted a 2 × 2 experiment with the factors collaboration script and heuristic worked examples with N = 101 math teacher students. Results showed that the learners’ engagement in self-generated dialectic transactivity (i.e., responding to the learning partner’s contribution in an argumentative way by critiquing and/or integrating their learning partner’s contributions) mediated the effects of both scaffolds on their disposition to use argumentation skills, whereas partner-generated dialectic transactivity or any other measured collaborative learning activity did not. To support the disposition to use argumentation skills in mathematics, learning environments should thus be designed in a way to help learners display dialectic transactivity. Future research should investigate how learners might better benefit from the dialectic transactivity generated by their learning partners

Feasibility of a multidimensional home-based exercise programme for the elderly with structured support given by the general practitioner's surgery: Study protocol of a single arm trial preparing an RCT [ISRCTN58562962]

<p>Abstract</p> <p>Background</p> <p>Physical activity programmes can help to prevent functional decline in the elderly. Until now, such programmes use to target either on healthy community-dwelling seniors or on elderly living in special residences or care institutions. Sedentary or frail people, however, are difficult to reach when they live in their own homes. The general practitioner's (GP) practice offers a unique opportunity to acquire these people for participation in activity programmes. We conceptualised a multidimensional home-based exercise programme that shall be delivered to the target group through cooperation between GPs and exercise therapists. In order to prepare a randomised controlled trial (RCT), a feasibility study is being conducted.</p> <p>Methods</p> <p>The study is designed as a single arm interventional trial. We plan to recruit 90 patients aged 70 years and above through their GPs. The intervention lasts 12 weeks and consists of physical activity counselling, a home-exercise programme, and exercise consultations provided by an exercise therapist in the GP's practice and via telephone. The exercise programme consists of two main components: 1. a combination of home-exercises to improve strength, flexibility and balance, 2. walking for exercise to improve aerobic capacity. Primary outcome measures are: appraisal by GP, undesirable events, drop-outs, adherence. Secondary outcome measures are: effects (a. motor tests: timed-up-and-go, chair rising, grip strength, tandem stand, tandem walk, sit-and-reach; b. telephone interview: PRISCUS-Physical Activity Questionnaire, Short Form-8 Health Survey, three month recall of frequency of falls, Falls Efficacy Scale), appraisal by participant, exercise performance, focus group discussion. Data analyses will focus on: 1. decision-making concerning the conduction of a RCT, 2. estimation of the effects of the programme, detection of shortcomings and identification of subgroups with contrary results, 3. feedback to participants and to GPs.</p> <p>Conclusion</p> <p>A new cooperation between GPs and exercise therapists to approach community-dwelling seniors and to deliver a home-exercise programme is object of research with regard to feasibility and acceptance. In case of success, an RCT should examine the effects of the programme. A future implementation within primary medical care may take advantage from the flexibility of the programme.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN58562962.</p

Openness in participation, assessment, and policy making upon issues of environment and environmental health: a review of literature and recent project results

Issues of environment and environmental health involve multiple interests regarding e.g. political, societal, economical, and public concerns represented by different kinds of organizations and individuals. Not surprisingly, stakeholder and public participation has become a major issue in environmental and environmental health policy and assessment. The need for participation has been discussed and reasoned by many, including environmental legislators around the world. In principle, participation is generally considered as desirable and the focus of most scholars and practitioners is on carrying out participation, and making participation more effective. In practice also doubts regarding the effectiveness and importance of participation exist among policy makers, assessors, and public, leading even to undermining participatory practices in policy making and assessment

Histone deacetylases in viral infections

Chromatin remodeling and gene expression are regulated by histone deacetylases (HDACs) that condense the chromatin structure by deacetylating histones. HDACs comprise a group of enzymes that are responsible for the regulation of both cellular and viral genes at the transcriptional level. In mammals, a total of 18 HDACs have been identified and grouped into four classes, i.e., class I (HDACs 1, 2, 3, 8), class II (HDACs 4, 5, 6, 7, 9, 10), class III (Sirt1–Sirt7), and class IV (HDAC11). We review here the role of HDACs on viral replication and how HDAC inhibitors could potentially be used as new therapeutic tools in several viral infections